Elucidating the within- and between-host adaptations driving S. aureus persistence within the bladder of long-term catheterized individuals

University Of Texas Hlth Sci Ctr Houston, Houston TX

Investigators

Abstract

PROJECT SUMMARY/ ABSTRACT Urinary catheterization is among the most common medical procedures in the US. Up to 22% of long-term care residents and 60% of critically ill patients receive a urinary catheter (UC) due to its efficacy at improving patient quality of life (QOL). However, urinary catheterization increases the risk (7% per day) of developing asymptomatic bacteriuria (ASB) and virtually all long-term UCs (>30 days) become colonized. ASB increases the risk of developing symptomatic catheter associated urinary tract infections (CAUTIs), which are currently the most common hospital-associated infection in the US and account for 1 million cases annually. In contrast to urinary tract infections (UTIs) in healthy individuals, CAUTIs and ASB are caused by a wide range of uropathogens that are often multidrug resistant (MDR), which complicates empiric treatment. For individuals with long-term UCs, ASB can serve as a reservoir, as these MDR uropathogens can persist for weeks despite antimicrobial treatment and UC changes. Problematically, the urinary tract is the most common source of secondary bacteremia in the hospital, as the bladder provides a direct route for these MDR pathogens to the bloodstream. Despite the wide range of CAUTI and ASB uropathogens, most studies still focus on the most common UTI pathogen, Escherichia coli, and other Gram-negative bacteria. Importantly, recent studies emphasize the importance of Gram-positive bacteria in CAUTI and ASB. Staphylococcus aureus is of particular concern as it i) is one of the most frequent causes of ASB, i) is typically methicillin resistant (MRSA), is found causing severe disease more often than other uropathogens, and iii) can block long-term UCs via urease produced crystal formation, which increases the frequency of UC changes needed, thereby decreasing QOL. As the US population continues to age, long-term UCs and subsequently MRSA CAUTI will become more common, highlighting the need for studies in this area. Surprisingly, few studies have investigated MRSA during CAUTI and no study has investigated how MRSA adapts during long-term ASB or how that adaptation affects pathogenicity. My genomic analyses of serial S. aureus strains from individuals with long-term UCs demonstrate that only a handful of genomic changes occur within strains that persist for months. Further analyses of mutations within a subset of these isolates demonstrate several genes (involved in metabolism, antibiotic resistance, and virulence) are under selection. Consistent with these findings, urease activity among serial S. aureus UC- associated strains increases over time. Thus, I hypothesize that as S. aureus persists within the catheterized bladder, genomic changes within antibiotic resistance and virulence genes promote pathogenicity and persistence. I will utilize our collection of S. aureus isolates to test this hypothesis through the following aims: i) identify the within- and between-host genomic adaptions driving persistence in long-term UCs and ii) assess the impact of genomic adaptions on pathogenicity and persistence. The completion of this proposal will identify genomic adaptations that may be used as biomarkers to better manage MRSA CAUTI.